Project Summary Heterobiaryls are an important class of substructures found in a large number of biologically active molecules and FDA approved drugs. These scaffolds are typically constructed through traditional cross-coupling strategies. Unfortunately, these protocols are inefficient for the incorporation of heteroaryl fragments. The objective of the work proposed here is to develop a fundamental understanding of the cross-coupling reactions of heteroarenes. We also aim to apply our findings to the development of new efficient and predictable cross-coupling reactions of heteroaromatic coupling partners. This work will ultimately allow synthetic and medicinal chemists to design predictable and reliable synthetic strategies to access these biologically relevant intermediates and target compounds. We recently identified the field effect of ortho- substituents as being a dominant predictor in the rate of decarboxylation and oxidative decarboxylative coupling (ODC) reactions of benzoic acids. The first phase of research will extend this predictive power to the ODC reactions of heteroaromatic carboxylates and benzoates without the typically required ortho-substituents. We hypothesize that new ligand scaffolds can be designed to mitigate the need for ortho-substituents in these reactions because the field effect parameter describes a through-space influence. In the final phase of our study, we will apply these new ligand structures to other classes of cross-coupling reactions that have historically suffered from related ortho-substituent limitations. The development of a large collection of predictable and reliable cross-coupling reactions that operate efficiently for a broad scope of (hetero)aromatic coupling partners is significant because it provides access to a large library of biologically relevant core structures. Thus, the development of a fundamental understanding of the trends and limitations in these and other coupling reactions of heteroarenes would allow existing and developing synthetic methods to be adapted for the construction of complex and pharmaceutically relevant structures.